Compositions and methods for inhibiting cytochrome p450 2d6

ABSTRACT

Methods of inhibiting cytochrome P450 2D6 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450 2D6. Pharmaceutical compositions are provided that can act as boosters to improve the pharmacokinetics, enhance the bioavailability, and enhance the therapeutic effect of drugs that undergo in vivo degradation by cytochrome P450 2D6 enzymes.

This application claims priority to provisional application Ser. No.60/990,868 filed Nov. 28, 2007, the contents of which are hereinincorporated by reference in their entirety. Compounds and methods forinhibiting cytochrome P450 2D6 enzymes are provided. Also provided aremethods of enhancing the therapeutic effect of drugs that aremetabolized by cytochrome P450 2D6 enzymes, methods of decreasing thetoxic effects of drugs that are metabolized to toxic by-products bycytochrome P450 2D6 enzymes, methods of increasing oral bioavailabilityof drugs that are metabolized by cytochrome P450 2D6 enzymes, andmethods of curing diseases that are caused or exacerbated by theactivity of cytochrome P450 2D6 enzymes.

BACKGROUND

Cytochrome P450s (P450) are a family of enzymes involved in theoxidative metabolism of both endogenous and exogenous compounds. P4502D6 enzymes are widely distributed in the liver, intestines and othertissues (Krishna et al., Clinical Pharmacokinetics. 26:144-160, 1994).P450 2D6 enzymes catalyze the phase I reaction of drug metabolism, togenerate metabolites for excretion. The classification of P450s is basedon homology of the amino acid sequence (Slaughter et al The Annals ofPharmacotherapy 29:619-624, 1995). In mammals, there is over 55%homology of the amino acid sequence of CYP450 subfamilies. Thedifferences in amino acid sequence constitute the basis for aclassification of the superfamily of cytochrome P450 2D6 enzymes intofamilies, subfamilies and isozymes.

Cytochrome P450 contains an iron cation and is a membrane bound enzymethat can carry out electron transfer and energy transfer. CytochromeP450, when bound to carbon monoxide (CO), displays a maximum absorbance(peak) at 450 nm in the visible spectra, and is therefore called P450(Omura et al., J. Biol. Chem. 239:2370, 1964).

Over 200 genes encoding cytochrome P450s have been identified, and aredivided among over 30 gene families. These gene families are organizedinto subfamilies, which vary in regulation of gene expression and inamino acid sequence homology, substrate specificity, catalytic activity,and physiological role of the encoded enzymes.

The efficacy of a drug can be dramatically affected by its metabolism inthe body. For drugs that are rapidly metabolized it can be difficult tomaintain an effective therapeutic dose in the body, and the drug oftenmust be given more frequently, in higher dose, and/or be administered ina sustained release formulation. Moreover, in the case of compounds fortreating infectious disease, such as viral or bacterial infections, theinability to maintain an effective therapeutic dose can lead to theinfectious agent becoming drug resistant. Many compounds that havestrong biological efficacy and that would otherwise be potentiallypowerful therapeutics are rendered essentially useless by virtue oftheir short half-lives in vivo. A common pathway of metabolism for drugsis via oxidation by one or more cytochrome P450 2D6 enzymes. Theseenzymes metabolize a drug to a more polar derivative that is morereadily excreted through the kidney or liver. First pass metabolismrefers to the elimination of drugs via liver and intestinal CYP450 2D6enzymes. First pass metabolism can lead to poor drug absorption from theGI tract due to extensive intestinal CYP450 metabolism, low plasma bloodlevels due to hepatic CYP450 metabolism, or both. Poor oralbioavailability due to CYP450 metabolism is a major reason for thefailure of drugs candidates in clinical trials. In some instances,metabolic by-products of CYP450 2D6 enzymes are highly toxic and canresult in severe side effects, cancer, and even death.

Some examples of drugs affected by CYP450 2D6 enzymes includesantidepressants (imipramine, clomipramine, desimpramine), antipsychotics(haloperidol, perphenazine, risperidone, thioridazine), beta blockers(carvedilol, S-metoprolol, propafenone, timolol), amphetamine, codeine,dextromethorphan, fluoxetine, S-mexiletine, phenacetin, propranolol.

Some examples of the effects of drug metabolism by CYP450 2D6 include

Dextromethorphan: CYP2D6 metabolizes dextromethrophan to dextrorphan.Individuals who express high levels of CYP2D6 (so-called rapidmetabolizers) do not receive therapeutic benefits from dextromethorphandue to extensive first-pass metabolism and rapid systemic clearance.

Protease Inhibitors: Protease inhibitors and non-nucleoside reversetranscriptase inhibitors currently indicated for use in treatment of HIVor HCV are typically good substrates of cytochrome P450 2D6 enzymes; inparticular, they are metabolized by CYP3A4 enzymes (see e.g. Sahai, AIDS10 Suppl 1:S21-5, 1996) with possible participation by CYP2D6 enzymes(Kumar et al., J. Pharmacol. Exp. Ther. 277(1):423-31, 1996). Althoughprotease inhibitors are reported to be inhibitors of CYP3A4, somenon-nucleoside reverse transcriptase inhibitors, such as nevirapine andefavirenz, are inducers of CYP3A4 (see e.g. Murphy et al., Expert OpinInvest Drugs 5/9: 1183-99, 1996).

Human CYP450 isozymes are widely distributed among tissues and organs(Zhang et al., Drug Metabolism and Disposition. 27:804-809, 1999). Withthe exception of CYP1A1 and CYP2A13, most human CYP450 isozymes arelocated in the liver, but are expressed at different levels (Waziers J.Pharmacol. Exp. Ther. 253: 387, 1990). A solution to the problem of drugdegradation and first-pass metabolism is to control the rate of drugmetabolism. When the rates of drug absorption and metabolism reach asteady state, a maintenance dose can be delivered to achieve a desireddrug concentration that is required for drug efficacy. Certain naturalproducts have been shown to increase bioavailability of a drug. Forexample, the effect of grapefruit juice on drug pharmacokinetics is wellknown. See Edgar et al., Eur. J. Clin. Pharmacol. 42:313, (1992); Lee etal., Clin. Pharmacol. Ther. 59:62, (1996); Kane et al., Mayo ClinicProc. 75:933, (2000). This effect of grapefruit juice is due to thepresence of natural P450-inhibiting components. Other compounds alsohave been used for inhibition of P450. For example, the HIV-1 proteaseinhibitor Ritonavir® is now more commonly prescribed for use incombination with other, more effective, HIV protease inhibitors becauseof its ability to “boost” those other compounds by inhibitingP450-mediated degradation.

SUMMARY OF THE INVENTION

Compounds and methods of inhibiting cytochrome P450 2D6 enzymes areprovided. Also provided are methods of enhancing the therapeutic effectof drugs that are metabolized by cytochrome P450 2D6 enzymes, methods ofdecreasing the toxic effects of drugs that are metabolized to toxicby-products by cytochrome P450 2D6 enzymes, methods of increasing oralbioavailability of drugs that are metabolized by cytochrome P450 2D6enzymes, and methods of curing diseases that are caused or exacerbatedby the activity of cytochrome P450 2D6 enzymes.

An advantage of the invention is that it provides improved inhibitors ofcytochrome P450 2D6 enzymes. Another advantage is that it provides amethod of controlling the pharmacokinetic properties of drugs. Anotheradvantage is that it helps control the rate of metabolism of drugs.Another advantage is that it controls the degradation of drugs. Anotheradvantage is that it enhances the bioavailability of drugs. Anotheradvantage is that it enhances the efficacy of drugs. Another advantageis that it boosts the efficacy of certain drugs so that the drugs can beadministered at a lower concentration or dosage thereby reducing theirtoxicity. Another advantage is that these properties can lower theoverall cost associated with the treatment of disorders.

More particularly, in one aspect, there is provided a compoundrepresented by a formula:

where J includes a basic amino group and 1 to 8 carbon atoms optionallycontaining from 1 to 3 heteroatoms independently selected from the groupconsisting of O, S, and N; or a salt form thereof; and where thecompound inhibits cytochrome P450 2D6 enzyme.

In another aspect, there is provided a method of inhibiting cytochromeP450 2D6 enzyme including administering to a patient a compoundincluding a benzofuran moiety attached on its benzene ring via a linkerto a basic amino group or a salt form thereof.

In yet another aspect, there is provided a pharmaceutical formulationincluding a pharmaceutically acceptable diluent, adjuvant or excipient,and a therapeutically effective amount of a compound including abenzofuran moiety attached on its benzene ring via a linker to a basicamino group or a salt form thereof.

In various examples, any of the aspects above or any of the methods orsystems or modules described herein, can include one or more of thefollowing features.

In one embodiment, there is provided compound represented by theformula:

In some embodiments, there is provided the compound where J includes:

J′-N(D)-SO_(n)—, J′-N(D)-CO_(n)—, J′-N(D)-(R)_(q)—, or

J′-N(D)-(R)_(q)—; wheren=1-2;q=0-1;D is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,heteroaryl, heteroaralkyl or aralkyl, O-alkyl, O-cycloalkyl,O-cycloalkylalkyl, O-heterocycloalkyl, O-heterocycloalkylalkyl,O-heteroaralkyl O-aralkyl, N(R)-alkyl, N(R)-cycloalkyl,N(R)-cycloalkylalkyl, N(R)-heterocycloalkyl, N(R)-heterocycloalkylalkyl,N(R)-heteroaralkyl, N(R)-aralkyl, where D optionally is substituted byalkyl, halo, nitro, cyano, O-alkyl, or S-alkyl;J′ is selected from acyl, sulfono, aminoalkyl, arylaminoalkyl,heteroarylaminoalkyl, aralkylaminoalkyl, heteroaralkylaminoalkyl, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyl or aralkyl,O-alkyl, O-cycloalkyl, O-cycloalkylalkyl, O-heterocycloalkyl,O-heterocycloalkylalkyl, O-heteroaralkyl O-aralkyl, N(R)-alkyl,N(R)-cycloalkyl, N(R)-cycloalkylalkyl, N(R)-heterocycloalkyl,N(R)-heterocycloalkylalkyl, N(R)-heteroaralkyl, N(R)-aralkyl, each ofthe substituents optionally substituted by alkyl, halo, nitro, cyano,O-alkyl, or S-alkyl; andR is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl.

In some embodiments, D is hydrogen, where R is alkyl and q=1, where Jincludes J′-N(D)-SO₂—, where J includes J′-N(D)-CO—, where R is CH2 andq=1, where J′ is aminoalkyl, where J′ is arylaminoalkyl, where J′ isheteroarylaminoalkyl, where J′ is aralkylaminoalkyl, where J′ isheteroaralkylaminoalkyl, where J includes an —NH— group or a salt formthereof.

In certain embodiments, the compound can include any combination of theabove groups.

There also is provided a compound having the structure:

where X is [—N(D)-SO_(n)—]_(q), where n is 1 or 2 and q is 0 or 1; R′may be C₁-C₆ alkyl when q is 0, or C₂-C₆ alkyl when q is 1, where R′optionally is substituted by up to 3 substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, OH, O-alkyl, alkylamido,alkylcarbamoyl, halo, nitro, cyano, S-alkyl, aralkyl and heteroaralkyl;each D independently may be is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyl and aralkyl; R″is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl-C₁-C₆-alkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkylor aralkyl, optionally substituted by up to 3 substituents independentlyselected from the group consisting of OH, O-alkyl, alkylamido,alkylcarbamoyl, halo, nitro, cyano, S-alkyl, aralkyl and heteroaralkyl.In one embodiment q is 0, and R′ is methylene. In this embodiment D maybe H or heteroaralkyl. and R″ may be s heteroaryl, heteroaralkyl, oroptionally substituted C₁-C₆ alkyl. In a specific embodiment, R″ may bealkylcarbamoyl substituted C₁-C₆ alkyl.

In another embodiment, q is 1, D is H or alkyl, and R″ may be alkyl. Inthese methods, the compound may be selected from the group consistingof:

In various embodiments, the linker is at the 5-position of thebenzofuran moiety, or where the basic amino group is a secondary ortertiary amine.

In certain embodiments, there is provided a method that can furtherinclude administering to a patient a compound represented by a formula:

In some embodiments, the compound is selected from:

In various embodiments, the method further includes administering thecompound prior to or substantially contemporaneously with a drug, whereefficacy of the drug is compromised due to degradation by cytochromeP450 2D6 enzyme. The drug may be dextromethorphan.

In certain embodiments, there is provided a pharmaceutical formulationwhere the compound is a cytochrome P450 2D6 inhibitor.

In various embodiments, the pharmaceutical formulation may inhibit themetabolism of dextromethorphan.

In some embodiments, the compound represented by the formula

can include:

a group containing from 1 to 12 carbon atoms optionally containing from1 to 3 heteroatoms independently selected from the group consisting ofO, S, and N,

—OCON(R2)-, —S(O)_(n)N(R2)-, —CON(R2)-, —COCO(NR2)-, —N(R2)CON(R2)-,—N(R2)S(O)_(n)N(R2)-, N(R2)CO or —N(R2)COO—;

—(CG₁G₂)_(m)-, where m is 0-6 and where G₁ and G₂ are the same ordifferent and where each G₁ and G₂ independently is selected from thegroup consisting of a bond, H, halo, haloalkyl, OR, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aralkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, and optionally substituted heterocycloalkylwhere each optional substitution independently is selected from thegroup consisting of alkyl, halo, cyano, CF₃, OR, C₃-C₇ cycloalkyl, C₅-C₇cycloalkenyl, R6, OR2, SR2, N(R2)₂, OR3, SR3, NR2R3, OR6, SR6, andNR2R6, and where G₁ and G₂, together with the atoms to which they areattached, optionally may form a 3-7-membered carbocyclic or heterocyclicring containing up to three heteroatoms selected from the groupconsisting of N, S and O, and where the ring optionally may besubstituted with up to 3 R7 moieties,

where M is selected from the group consisting of: a bond, OC(R8)_(q),—CO—, —SO_(n)—, —O—, —O—CO—, —N(D)-SO_(n)—, —N(D)-CO_(n)—,—N(D)-(R8)_(q)-, —SO_(n)—N(D)-(R8)_(q)-, or —CO_(n)—N(D)-(R8)_(q)-,

where M can be linked in either orientation with respect to thebenzofuran ring,

where D is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,heteroaryl, heteroaralkyl or aralkyl, O-alkyl, where D optionally issubstituted by alkyl, halo, nitro, cyano, O-alkyl, or S-alkyl;

where R is H, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl;

where each R2 is independently selected from the group consisting of H,C₁-C₁₂ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, and heterocycloalkyl each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

or each R2 is independently selected from the group consisting of C₁-C₆alkyl; substituted by aryl or heteroaryl; which groups optionally aresubstituted with one or more substituents selected from the groupconsisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR;

R3 is C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, or heterocyclo; which groups optionally are substitutedwith one or more substituents selected from the group consisting ofhalo, OR2, R2-OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2,N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂,N(R2)N(R2)CO_(n)R2, oxo, ═N—OR2, ═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂,═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂, and ═NNR2S(O)_(n)(R2);

R6 is aryl or heteroaryl, where the aryl or heteroaryl optionally aresubstituted with one or more groups selected from the group consistingof aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO₂, CN,CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂,S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2,NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, OC(O)R2, OC(S)R2, OC(O)N(R2)₂,and OC(S)N(R2)₂;

R7 is H, oxo, C₁-C₁₂ alkyl; C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or heterocycloalkyl, each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

R8 is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl;

where n=1-2, and q=0-1,

where the benzene ring of the benzofuran moiety may optionally bysubstituted by up to three substituents independently selected from thegroup consisting of R2, halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, andNRPO_(n)OR, where the up to three substituents do not form a ringbetween any adjacent carbon atoms of the benzene ring, and with theproviso that the compound does not contain a basic aliphatic aminefunction and does not contain a carboxylic acid group.

In the methods described above, the cytochrome P450 monoxygenase may beCYP2D6.

In specific embodiments, the patient may be suffering from chronic pain,depression, epilepsy, psychosis, inflammation, cancer, cardiovasculardisease, diabetes, and/or infection, for example, infection with ahepatitis-causing virus or HIV.

In other embodiments, the compound is administered substantiallycontemporaneously with a drug where efficacy of the drug is compromiseddue to degradation by cytochrome P450 2D6.

The details of one or more examples are set forth in the accompanyingreaction schemes and description. Further features, aspects, andadvantages of the invention will become apparent from the description,the schemes, and the claims.

DETAILED DESCRIPTION

Compounds and method for inhibiting cytochrome P450 2D6 enzymes areprovided. More particularly, methods are provided for enhancing thetherapeutic effect of drugs in which the efficacy is compromised due todegradation mediated by cytochrome P450. The methods includeadministering compounds or pharmaceutical compositions containing thecompounds in any therapeutic regimen where one or more primary drugs ismetabolized by a CYP. The compounds or pharmaceutical compositions canbe administered when the primary drug either becomes inactive or isconverted to a toxic metabolite due to metabolism by a CYP. Thecompounds or compositions can inhibit or reduce the rate of degradationof drugs that are effective against a variety of diseases and that aredegraded by cytochrome P450 2D6 enzymes. Upon co-administration, thecompounds and compositions can, for example, maintain intracellularconcentrations of the drugs at a therapeutic level for a sustainedperiod of time. The methods are useful, for example, in treating avariety of disorders such as, cardiac arrhythmia, depression, psychosis,chronic pain, and infections such as HIV or HCV. The compounds orcompositions can be administered either alone or in combination withdrugs such as analgesics, anti-depressants, anti-psychotics,antibiotics, anti-arrythmics, steroids, anesthetics, muscle relaxants,cardiac stimulants, NSAIDs, anti-epileptics, or protease inhibitors,such as HIV or HCV protease inhibitors.

In particular, there is provided a method of inhibiting cytochrome P4502D6 enzyme by administering to a patient, a compound represented by aformula:

where J includes a basic amino group and 1 to 8 carbon atoms optionallycontaining from 1 to 3 heteroatoms independently selected from the groupconsisting of O, S, and N;or a salt form thereof; and where the compound inhibits cytochrome P4502D6 enzyme.

In one embodiment, the compound may be represented by the formula:

In some embodiments, J may include:

J′-N(D)-SO_(n)—, J′-N(D)-CO_(n)—, J′-N(D)-(R)_(q)-, or

J′-N(D)-(R)_(q)-; wheren=1-2;q=0-1;D is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,heteroaryl, heteroaralkyl or aralkyl, O-alkyl, O-cycloalkyl,O-cycloalkylalkyl, O-heterocycloalkyl, O-heterocycloalkylalkyl,O-heteroaralkyl O-aralkyl, N(R)-alkyl, N(R)-cycloalkyl,N(R)-cycloalkylalkyl, N(R)-heterocycloalkyl, N(R)-heterocycloalkylalkyl,N(R)-heteroaralkyl, N(R)-aralkyl, where D optionally is substituted byalkyl, halo, nitro, cyano, O-alkyl, or S-alkyl;J′ is selected from acyl, sulfono, aminoalkyl, arylaminoalkyl,heteroarylaminoalkyl, aralkylaminoalkyl, heteroaralkylaminoalkyl, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyl or aralkyl,O-alkyl, O-cycloalkyl, O-cycloalkylalkyl, O-heterocycloalkyl,O-heterocycloalkylalkyl, O-heteroaralkyl O-aralkyl, N(R)-alkyl,N(R)-cycloalkyl, N(R)-cycloalkylalkyl, N(R)-heterocycloalkyl,N(R)-heterocycloalkylalkyl, N(R)-heteroaralkyl, N(R)-aralkyl, each ofthe substituents optionally substituted by alkyl, halo, nitro, cyano,O-alkyl, or S-alkyl; and

R is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl.

In some embodiments, D is hydrogen, where R is alkyl and q=1, where Jincludes J′-N(D)-SO₂—, where J includes J′-N(D)-CO—, where R is CH₂ andq=1, where J′ is aminoalkyl, where J′ is arylaminoalkyl, where J′ isheteroarylaminoalkyl, where is aralkylaminoalkyl, where J′ isheteroaralkylaminoalkyl, where J includes an —NH— group or a salt formthereof.

In certain embodiments, the compound may include any combination of theabove groups.

There also is provided a compound having the structure:

where:X is [—N(D)-SO_(n)—]_(q), where n is 1 or 2 and q is 0 or 1;R′ may be C₁-C₆ alkyl when q is O, or C₂-C₆ alkyl when q is 1, where R′optionally is substituted by up to 3 substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, OH, O-alkyl, alkylamido,alkylcarbamoyl, halo, nitro, cyano, S-alkyl, aralkyl and heteroaralkyl;each D independently may be is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyl and aralkyl;R″ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl-C₁-C₆-alkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkylor aralkyl, optionally substituted by up to 3 substituents independentlyselected from the group consisting of OH, O-alkyl, alkylamido,alkylcarbamoyl, halo, nitro, cyano, S-alkyl, aralkyl and heteroaralkyl.In specific embodiments q is 0, and R′ is methylene; D may be H orheteroaralkyl. and R″ may be s heteroaryl, heteroaralkyl, or optionallysubstituted C₁-C₆ alkyl. In a specific embodiment, R″ may bealkylcarbamoyl substituted C₁-C₆ alkyl.

In another embodiment, q is 1, D is H or alkyl, and R″ may be alkyl. Inthese methods, the compound may be selected from the group consistingof:

In one aspect, there are provided methods of inhibiting cytochrome P4502D6 enzyme including administering to a patient a compound including abenzofuran moiety attached on its benzene ring via a linker to a basicamino group or a salt form thereof.

In various embodiments, the linker is at the 5-position of thebenzofuran moiety, or where the basic amino group is a secondary ortertiary amine.

In certain embodiments, the method may further include administering toa patient a compound represented by a formula:

In some embodiments, the compound is selected from:

In various embodiments, there are provided methods further includingadministering the compound prior to or substantially contemporaneouslywith a drug, where efficacy of the drug is compromised due todegradation by cytochrome P450 2D6 enzyme.

In certain embodiments, the drug whose metabolism is inhibited isdextromethorphan.

In another aspect, there is provided a pharmaceutical formulationincluding a pharmaceutically acceptable diluent, adjuvant or excipient,and a therapeutically effective amount of a compound including abenzofuran moiety attached on its benzene ring via a linker to a basicamino group or a salt form thereof.

In certain embodiments, the compound is a cytochrome P450 2D6 inhibitor.

In various embodiments, there is provided a pharmaceutical formulationwhere the compound inhibits the metabolism of dextromethorphan.

In some embodiments, the compound represented by the formula

can include:

a group containing from 1 to 12 carbon atoms optionally containing from1 to 3 heteroatoms independently selected from the group consisting ofO, S, and N,

—OCON(R2)-, —S(O)_(n)N(R2)-, —CON(R2)-, —COCO(NR2)-, —N(R2)CON(R2)-,—N(R2)S(O)_(n)N(R2)-, N(R2)CO or —N(R2)COO—;

—(CG₁G₂)_(m)-, where m is 0-6 and where G₁ and G₂ are the same ordifferent and where each G₁ and G₂ independently is selected from thegroup consisting of a bond, H, halo, haloalkyl, OR, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aralkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, and optionally substituted heterocycloalkylwhere each optional substitution independently is selected from thegroup consisting of alkyl, halo, cyano, CF₃, OR, C₃-C₇ cycloalkyl, C₅-C₇cycloalkenyl, R6, OR2, SR2, N(R2)₂, OR3, SR3, NR2R3, OR6, SR6, andNR2R6, and where G₁ and G₂, together with the atoms to which they areattached, optionally may form a 3-7-membered carbocyclic or heterocyclicring containing up to three heteroatoms selected from the groupconsisting of N, S and O, and where the ring optionally may besubstituted with up to 3 R7 moieties,

where M is selected from the group consisting of: a bond, OC(R8)_(q),—CO—, —SO_(n)—, —O—, —O—CO—, —N(D)-SO_(n)—, —N(D)-CO_(n)—,—N(D)-(R8)_(q)-, —SO_(n)—N(D)-(R8)_(q)-, or —CO_(n)—N(D)-(R8)_(q)-,

where M can be linked in either orientation with respect to thebenzofuran ring,

where D is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,heteroaryl, heteroaralkyl or aralkyl, O-alkyl, where D optionally issubstituted by alkyl, halo, nitro, cyano, O-alkyl, or S-alkyl;

where R is H, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl;

where each R2 is independently selected from the group consisting of H,C₁-C₁₂ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, and heterocycloalkyl each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, —NNRC(O)N(R)₂, —NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

or each R2 is independently selected from the group consisting of C₁-C₆alkyl; substituted by aryl or heteroaryl; which groups optionally aresubstituted with one or more substituents selected from the groupconsisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR;

R3 is C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, or heterocyclo; which groups optionally are substitutedwith one or more substituents selected from the group consisting ofhalo, OR2, R2-OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2,N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂,N(R2)N(R2)CO_(n)R2, oxo, ═N—OR2, ═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂,═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂, and ═NNR2S(O)_(n)(R2);

R6 is aryl or heteroaryl, where the aryl or heteroaryl optionally aresubstituted with one or more groups selected from the group consistingof aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO₂, CN,CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂,S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2,NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, OC(O)R2, OC(S)R2, OC(O)N(R2)₂,and OC(S)N(R2)₂;

R7 is H, oxo, C₁-C₁₂ alkyl; C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or heterocycloalkyl, each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

R8 is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl;

where n=1-2, and q=0-1,

where the benzene ring of the benzofuran moiety may optionally bysubstituted by up to three substituents independently selected from thegroup consisting of R2, halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, andNRPO_(n)OR, where the up to three substituents do not form a ringbetween any adjacent carbon atoms of the benzene ring, and with theproviso that the compound does not contain a basic aliphatic aminefunction and does not contain a carboxylic acid group.

In specific embodiments, the patient may be suffering from chronic pain,depression, epilepsy, psychosis, inflammation, cancer, cardiovasculardisease, diabetes, and/or infection, for example, infection with ahepatitis-causing virus or HIV.

In other embodiments, the compound is administered substantiallycontemporaneously with a drug where efficacy of the drug is compromiseddue to degradation by cytochrome P450 monooxygenase.

An exemplary and non-limiting group of compounds that can act ascytochrome P450 2D6 enzyme inhibitors is illustrated by the followingcompounds are:

The term “pharmaceutically effective amount” or “therapeuticallyeffective amount” or “therapeutic dose” or “efficacious dose” refers toan amount that when administered to a subject is effective in inhibitingcytochrome P450 enough to reduce or prevent the in vivo degradation of aco-administered drug and thereby improve the pharmacokinetics of thedrug and/or boost its efficacy. The term “treating” as used hereinrefers to the alleviation of symptoms of a particular disorder in asubject, such as a human patient, or the improvement of an ascertainablemeasurement associated with a particular disorder. The term“prophylactically effective amount” refers to an amount effective inpreventing a disease in a subject, such as a human patient. As usedherein, a “subject” refers to a mammal, including a human.

The term “substituted”, whether preceded by the term “optionally” ornot, and substitutions contained in formulas of this invention, includethe replacement of one or more hydrogen radicals in a given structurewith the radical of a specified substituent. When more than one positionin a given structure can be substituted with more than one substituentselected from a specified group, the substituents can be either the sameor different at every position (for example, in the moiety —N(R2)(R2),the two R2 substituents can be the same or different). Typically, when astructure can be optionally substituted, 0-3 substitutions arepreferred, and 0-1 substitution is more preferred. Advantageously, eachsubstituent enhances cytochrome P450 inhibitory activity in permissivemammalian cells, or enhances deliverability by improving solubilitycharacteristics or pharmacokinetic or pharmacodynamic profiles ascompared to the unsubstituted compound. Combinations of substituents andvariables envisioned by this invention are limited to those that resultin the formation of stable compounds.

The term “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture, formulation, andadministration to a mammal by methods known in the art. Typically, suchcompounds are stable at a temperature of 40° C. or less, in the absenceof moisture or other chemically reactive conditions, for at least aweek.

The term “alkyl”, alone or in combination with any other term, refers toa straight-chain or branched-chain saturated aliphatic hydrocarbonradical containing the specified number of carbon atoms, or where nonumber is specified, advantageously from 1 to about 12 or 1 to 15 carbonatoms. Examples of alkyl radicals include, but are not limited to:methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isoamyl, n-hexyl and the like.

The term “alkenyl”, alone or in combination with any other term, refersto a straight-chain or branched-chain mono- or poly-unsaturatedaliphatic hydrocarbon radical containing the specified number of carbonatoms, or where no number is specified, advantageously from 2-6 or 2-10carbon atoms. Alkenyl groups include all possible E and Z isomers unlessspecifically stated otherwise. Examples of alkenyl radicals include, butare not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl,pentenyl, hexenyl, hexadienyl and the like.

The term “alkynyl,” alone or in combination with any other term, refersto a straight-chain or branched-chain hydrocarbon radical having one ormore triple bonds containing the specified number of carbon atoms, orwhere no number is specified, advantageously from 2 to about 10 carbonatoms. Examples of alkynyl radicals include, but are not limited to,ethynyl, propynyl, propargyl, butynyl, pentynyl and the like.

The term “alkoxy” refers to an alkyl ether radical, where the term“alkyl” is as defined above. Examples of suitable alkyl ether radicalsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The terms “alkylamino” or “dialkylamino” include amino radicalssubstituted by one or two alkyl groups, where the term “alkyl” isdefined above, and the alkyl group can be the same or different.Examples of suitable alkylamino and dialkylamino radicals include, butare not limited to, methylamino, ethylamino, isoproylamino,dimethylamino, methylethylamino, ethylbutylamino and the like.

The term “hydroxyalkyl” refers to an alkyl radical as defined above inwhich one of the hydrogen atoms is replaced by hydroxy group. Examplesof suitable hydroxyalkyl radicals include, but are not limited to,hydroxymethyl, 2-hydroxypropyl and the like.

The term “alkoxyalkyl” refers to an alkyl radical as defined above inwhich one of the hydrogen atoms is replaced by an alkoxy radical asdefined above.

The terms “aminoalkyl”, “alkylaminoalkyl” or “dialkylaminoalkyl” refersto an alkyl radical as defined above in which one of the hydrogen atomsis replaced by an amino or “alkylamino” or “dialkylamino” radical asdefined above.

The term “halo” or “halogen” includes fluorine, chlorine, bromine oriodine.

The term “haloalkyl” includes alkyl groups with one or more of itshydrogens replaced by halogens.

The term “thioalkyl” includes alkyl radicals having at least one sulfuratom, where alkyl has the significance given above. An example of athioalkyl is CH₃SCH₂. The definition also encompasses the correspondingsulfoxide and sulfone of this thioalkyl CH₃S(O)CH₂ and CH₃S(O)₂CH₂respectively. Unless expressly stated to the contrary, the terms “—SO₂—”and “—S(O)₂—” as used herein include sulfone or sulfone derivative(i.e., both appended groups linked to the S), and not a sulfinate ester.

The terms “carboalkoxy” or “alkoxycarbonyl” include alkyl esters of acarboxylic acid. Examples of “carboalkoxy” or “alkoxycarbonyl” radicalsinclude, but are not limited to ethoxycarbonyl (or carboethoxy), Boc (ort-butoxycarbonyl), Cbz (or benzyloxycarbonyl) and the like.

The term “alkanoyl” includes acyl radicals derived from analkanecarboxylic acid. Examples of alkanoyl radicals include, but arenot limited to acetyl, propionyl, isobutyryl and the like.

The term “aryl,” alone or in combination with any other term, refers toa carbocyclic aromatic radical (such as phenyl or naphthyl) containingthe specified number of carbon atoms, preferably from 6-15 carbon atoms,and more preferably from 6-10 carbon atoms, optionally substituted withone or more substituents selected from alkyl, alkoxy, (for examplemethoxy), nitro, halo, amino, mono or dialkylamino, carboalkoxy, cyano,thioalkyl, alkanoyl, carboxylate, and hydroxy. Examples of aryl radicalsinclude, but are not limited to phenyl, p-tolyl, 4-hydroxyphenyl,1-naphthyl, 2-naphthyl, indenyl, indanyl, azulenyl, fluorenyl,anthracenyl and the like.

The term “aralkyl”, alone or in combination, includes alkyl radicals asdefined above in which one or more hydrogen atoms is replaced by an arylradical as defined above. Examples of aralkyl radicals include, but arenot limited to benzyl, 2-phenylethyl and the like.

The term “aralkanoyl” includes acyl radicals derived from anaryl-substituted alkanecarboxylic acid such as phenylacetyl,3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, (1-naphthyl)acetyl,4-methoxyhydrocinnamoyl, and the like.

The term “aroyl” includes acyl radicals derived from an aromaticcarboxylic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl,6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,3-(benzyloxyformamido)-2-naphthoyl, and the like.

The term “arylsulfonyl” includes sulfonyl radicals derived from anaromatic sulfonic acid such as benzenesulfonyl, 4-chlorobenzenesulfonyl,1-naphthalenesulfonyl, 2-naphthalenesulfonyl, and the like.

The term “carbocycle” refers to a non-aromatic stable 3- to 8-memberedcarbon ring which can be saturated, mono-unsaturated orpoly-unsaturated. The carbocycle can be attached at any endocycliccarbon atom which results in a stable structure. Preferred carbocycleshave 5-7 carbons.

The term “cycloalkyl”, alone or in combination, includes alkyl radicalswhich contain from about 3 to about 8 carbon atoms and are cyclic.Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like.

The term “cycloalkenyl” alone or in combination includes alkenylradicals as defined above which contain about 3-8 carbon atoms and arecyclic.

The term “cycloalkylalkyl” includes alkyl radicals as defined abovewhich are substituted by a cycloalkyl radical containing from about 3 toabout 8, preferably from about 3 to about 6, carbon atoms.

The term “heterocyclyl” or “heterocyclo” or “heterocycloalkyl” refers toa stable 3-7 membered monocyclic heterocycle or 8-11 membered bicyclicheterocycle which is either saturated or partially unsaturated, andwhich can be optionally benzofused if monocyclic and which is optionallysubstituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo,and the like, and/or on a secondary nitrogen atom (i.e., —NH—) by alkyl,aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiarynitrogen atom (i.e., +N—) by oxido and which is attached via a carbonatom. Each heterocycle consists of one or more carbon atoms and from oneto four heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. As used herein, the terms “nitrogen and sulfurheteroatoms” include oxidized forms of nitrogen and sulfur, and thequaternized form of any basic nitrogen. A heterocyclyl radical can beattached at any endocyclic carbon or heteroatom which results in thecreation of a stable structure. Preferred heterocycles include 5-7membered monocyclic heterocycles, and 8-10 membered bicyclicheterocycles. Examples of such groups imidazolinyl, imidazolidinyl,indazolinyl, perhydropyridazyl, pyrrolinyl, pyrrolidinyl, piperidinyl,pyrazolinyl, piperazinyl, morpholinyl, thiamorpholinyl, thiazolidinyl,thiamorpholinyl sulfone, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl,tetrahydropyranyl, tetrahydrofuranyl, dioxolyl, dioxinyl, benzodioxolyl,dithiolyl, tetrahydrothienyl, sulfolanyl, dioxanyl, dioxolanyl,tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl,dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl.

The term “heteroaryl” refers to stable 5-6 membered monocyclic or 8-11membered bicyclic or 13-16 membered tricyclic aromatic heterocycleswhere heterocycles is as defined above. Non-limiting examples of suchgroups include imidazolyl, quinolyl, isoquinolyl, indolyl, indazolyl,pyridazyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, quinoxolyl, pyranyl,pyrimidinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl,tetrazolyl, benzofuranyl, thiamorpholinyl sulfone, oxazolyl,benzoxazolyl, benzimidazolyl, benzthiazolyl, oxopiperidinyl,oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxazolyl, isothiazolyl,furazanyl, thiazolyl, thiadiazyl, oxathiolyl, acridinyl,phenanthridinyl, and benzocinnolinyl.

The term “heterocycloalkylalkyl” refers to an alkyl radical as definedabove which is substituted by a heterocycloalkyl radical as definedabove.

The term “heteroaralkyl” alone or in combination, includes alkylradicals as defined above in which one or more hydrogen atom is replacedby a hetoroaryl group as defined above.

As used herein, the compounds of this invention are defined to includepharmaceutically acceptable derivatives or prodrugs thereof. A“pharmaceutically acceptable derivative or prodrug” includes apharmaceutically acceptable salt, ester, salt of an ester, or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing (directly or indirectly) a compoundof this invention. Particularly favored derivatives and prodrugs arethose that increase the bioavailability of the compounds of thisinvention when such compounds are administered to a mammal (e.g., byallowing an orally administered compound to be more readily absorbedinto the blood) or which enhance delivery of the parent compound to abiological compartment (e.g., the brain or lymphatic system) relative tothe parent species. Examples of prodrugs of hydroxy containing compoundsare amino acid esters or phosphonate or phosphate esters that can becleaved in vivo hydrolytically or enzymatically to provide the parentcompound. These have the advantage of providing potentially improvedsolubility.

The compounds of this invention can contain one or more asymmetriccarbon atoms and thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Allsuch isomeric forms of these compounds are expressly included in theinvention. Each stereogenic carbon can be of the R or S configuration.Although the specific compounds exemplified in this application can bedepicted in a particular stereochemical configuration, compounds havingeither the opposite stereochemistry at any given chiral center ormixtures thereof are also envisioned.

Preparation of the Compounds

The compounds can be prepared according to synthetic methods known inthe art. For example, benzofuran sulfonamides may be prepared bycoupling of an amine to a benzofuranyl sulfonyl chloride. In otherexamples, basic amine compounds of the invention may be prepared byreductive amination reactions in which an amine and an aldehyde arereacted to form a Schiff's base, which is reduced with, for example,sodium borohydride, to form the desited amine. Other synthetic methodsthat can be used to prepare the subject compounds are set forth, forexample, in U.S. Pat. No. 6,319,946 to Hale et al., and in J. Med. Chem.36, 288-291 (93), the disclosures of which are incorporated herein byreference in their entireties, together with procedures of the typedescribed below.

Specific examples of syntheses of compounds of the invention include:

In this example, the secondary amino group of compound 1 is protected asan FMOC derivative, followed by deprotection of the primary amino groupto give compound 3, which then is reacted with the benzofuran sulfonylchloride 4 to give compound 5. Removal of the FMOC group with a basesuch as piperidine provides compound 6.

Another example is:

Here, the benzofuranyl aldehyde and the pyridyl amine are coupled via areductive amination reaction to provide compound 7.

A further example is:

The dimethylpropanediamine is reacted with the benzofuran sulfonylchloride to provide compound 8, which is reductively coupled withisobutyraldehyde to provide compound 9.

Use of Compounds for “Boosting”

Cytochrome P450 2D6 enzymes are responsible for the metabolicdegradation of a variety of drug molecules, thus disturbing theirpharmacokinetics and reducing their bioavailabilty. Compositions thatcan inhibit cytochrome P450 can therefore improve the pharmacokineticsand bioavailability of such drugs.

In certain embodiments, there are provided methods for inhibitingcytochrome P450 monooxygenase by administering to a patient, one or morecompounds described herein. The compound can function as a potentcytochrome P450 2D6 inhibitor and can improve the pharmacokinetics of adrug (or a pharmaceutically acceptable salt thereof) which ismetabolized by cytochrome P450 2D6. The compound or its pharmaceuticallyacceptable salt can be administered by itself or in combination with theother drug. When administered in combination, the two therapeutic agentscan be formulated as separate compositions which are administered at thesame time or different times, or the two therapeutic agents can beadministered as a single composition.

The compounds described above are effective for inhibiting a CYP 2D6enzyme. Use of the compounds of the invention therefore permits reducedrates of drug degradation and extended durations of action in vivo. Thecompounds are useful for “boosting” the activity of a variety of drugs.

Methods of Administration of Compounds

The compounds of the invention can be administered in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. Included among such acid salts, for example, are the following:acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Other pharmaceutically acceptable salts include salts with an inorganicbase, organic base, inorganic acid, organic acid, or basic or acidicamino acid. Inorganic bases which form the pharmaceutically acceptablesalts include alkali metals such as sodium or potassium, alkali earthmetals such as calcium and magnesium, aluminum, and ammonia. Organicbases which form pharmaceutically acceptable salts includetrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine. Inorganic acidswhich form the pharmaceutically acceptable salts include hydrochloricacid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid.Organic acids appropriate to form the salt include formic acid, aceticacid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid,maleic acid, citric acid, succinic acid, malic acid, methanesulfonicacid, benzenesulfonic acid, and p-toluenesulfonic acid. Basic aminoacids to form the salt include arginine, lysine and ornithine. Acidicamino acids to form the salt include aspartic acid and glutamic acid.

Also contemplated are compositions which can be administered orally ornon-orally in the form of, for example, granules, powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions, by mixing these effective components,individually or simultaneously, with pharmaceutically acceptablecarriers, excipients, binders, diluents or the like.

As a solid formulation for oral administration, the composition can bein the form of powders, granules, tablets, pills and capsules. In thesecases, the compounds can be mixed with at least one additive, forexample, sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran,starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum,gum arabic, gelatins, collagens, casein, albumin, synthetic orsemi-synthetic polymers or glycerides. The formulations can containfurther additives, for example, an inactive diluent, a lubricant such asmagnesium stearate, a preservative such as paraben or sorbic acid, ananti-oxidant such as ascorbic acid, tocopherol or cysteine, adisintegrator, a binder, a thickening agent, a buffer, a sweetener, aflavoring agent and a perfuming agent. Tablets and pills can further beprepared with enteric coating.

Examples of liquid preparations for oral administration includepharmaceutically acceptable emulsions, syrups, elixirs, suspensions andsolutions, which can contain an inactive diluent, for example, water.

As used herein, “non-orally” includes subcutaneous injection,intravenous injection, intramuscular injection, intraperitonealinjection or instillation. Injectable preparations, for example, sterileinjectable aqueous suspensions or oil suspensions can be prepared byknown procedures in the fields concerned, using a suitable dispersant orwetting agent and suspending agent. The sterile injections can be, forexample, a solution or a suspension, which is prepared with a non-toxicdiluent administrable non-orally, such as an aqueous solution, or with asolvent employable for sterile injection. Examples of usable vehicles oracceptable solvents include water, Ringer's solution and an isotonicaqueous saline solution. Further, a sterile non-volatile oil can usuallybe employed as solvent or suspending agent. A non-volatile oil and afatty acid can be used for this purpose, including natural or syntheticor semi-synthetic fatty acid oil or fatty acid, and natural or syntheticmono- or di- or tri-glycerides.

The pharmaceutical compositions can be formulated for nasal aerosol orinhalation and can be prepared as solutions in saline, and benzylalcohol or other suitable preservatives, absorption promoters,fluorocarbons, or solubilizing or dispersing agents.

Rectal suppositories can be prepared by mixing the drug with a suitablevehicle, for example, cocoa butter and polyethylene glycol, which is inthe solid state at ordinary temperatures, in the liquid state attemperatures in intestinal tubes and melts to release the drug.

The pharmaceutical composition can be formulated for topicaladministration with a suitable ointment containing one or more of thecompounds suspended or dissolved in a carrier, which include mineraloil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In addition, topical formulations can be formulated with a lotion orcream containing the active compound suspended or dissolved in acarrier. Suitable carriers include mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetaryl alcohol, 2-octyldodecanol,benzyl alcohol and water.

In some embodiments, the pharmaceutical compositions can include α-, β-,or γ-cyclodextrins or their derivatives. In certain embodiments,co-solvents such as alcohols can improve the solubility and/or thestability of the compounds in pharmaceutical compositions. In thepreparation of aqueous compositions, addition salts of the compounds canbe suitable due to their increased water solubility.

Appropriate cyclodextrins are α-, β-, or γ-cyclodextrins (CDs) or ethersand mixed ethers thereof where one or more of the hydroxy groups of theanhydroglucose units of the cyclodextrin are substituted withC₁-C₆alkyl, such as methyl, ethyl or isopropyl, e.g. randomly methylated(β-CD; hydroxy C₁₆ alkyl, particularly hydroxy-ethyl, hydroxypropyl orhydroxybutyl; carboxy C₁-C₆alkyl, particularly carboxymethyl orcarboxyethyl; C₁-C₆alkyl-carbonyl, particularly acetyl; C₁-C₆alkyloxycarbonylC₁-C₆alkyl or carboxyC₁-C₆alkyloxyC₁-C₆alkyl,particularly carboxymethoxypropyl or carboxyethoxypropyl;C₁-C₆alkylcarbonyloxyC₁-C₆alkyl, particularly 2-acetyloxypropyl.Complexants and/or solubilizers are β-CD, randomly methylated β-CD,2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD,hydroxy-propyl-γ-CD and (2-carboxymethoxy)propyl-β-CD, and2-hydroxy-propyl-β-CD (2-HP-β-CD) can be used.

The term “mixed ether” denotes cyclodextrin derivatives where at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxy-propyl and hydroxyethyl.

The compounds can be formulated in combination with a cyclodextrin or aderivative thereof as described in U.S. Pat. No. 5,707,975. Although theformulations described therein are with antifungal active ingredients,they are equally relevant for formulating compounds as described herein.The formulations described therein are particularly suitable for oraladministration and comprise an antifungal as active ingredient, asufficient amount of a cyclodextrin or a derivative thereof as asolubilizer, an aqueous acidic medium as bulk liquid carrier and analcoholic co-solvent that greatly simplifies the preparation of thecomposition. The formulations can also be rendered more palatable byadding pharmaceutically acceptable sweeteners and/or flavors.

Other methods to enhance the solubility of the compounds describedherein in pharmaceutical compositions are described in WO 94/05263, WO98/42318, EP-A-499,299 and WO 97/44014, all incorporated herein byreference.

In some embodiments, the compounds can be formulated in a pharmaceuticalcomposition comprising a therapeutically effective amount of particlesconsisting of a solid dispersion comprising a compound of formula I, andone or more pharmaceutically acceptable water-soluble polymers.

The term “solid dispersion” defines a system in a solid state comprisingat least two components, where one component is dispersed more or lessevenly throughout the other component or components. When the dispersionof the components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermodynamics, such a solid dispersion is referred to as “a solidsolution”. Solid solutions are preferred physical systems because thecomponents therein are usually readily bioavailable to the organisms towhich they are administered.

The term “solid dispersion” also includes dispersions which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase.

The water-soluble polymer in the particles can be a polymer that has anapparent viscosity of 1 to 100 mPa·s when dissolved in a 2% aqueoussolution at 20′C. Preferred water-soluble polymers are hydroxypropylmethylcelluloses (HPMC). HPMC having a methoxy degree of substitutionfrom about 0.8 to about 2.5 and a hydroxypropyl molar substitution fromabout 0.05 to about 3.0 are generally water soluble. Methoxy degree ofsubstitution refers to the average number of methyl ether groups presentper anhydroglucose unit of the cellulose molecule. Hydroxypropyl molarsubstitution refers to the average number of moles of propylene oxidewhich have reacted with each anhydroglucose unit of the cellulosemolecule.

The particles as defined hereinabove can be prepared by first preparinga solid dispersion of the components, and then optionally grinding ormilling that dispersion. Various techniques exist for preparing soliddispersions including melt-extrusion, spray-drying andsolution-evaporation.

The compounds can be formulated in the form of nanoparticles which havea surface modifier adsorbed on the surface thereof in an amountsufficient to maintain an effective average particle size of less than1000 nm. Useful surface modifiers are believed to include those whichphysically adhere to the surface of the antiretroviral agent but do notchemically bond to the antiretroviral agent.

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

The compounds can also be incorporated in hydrophilic polymers andapplied as a film over many small beads, thus yielding a compositionwith good bioavailability which can be manufactured and which issuitable for preparing pharmaceutical dosage forms for oraladministration. The beads comprise a central, rounded or spherical core,a coating film of a hydrophilic polymer and an antiretroviral agent anda seal-coating polymer layer. Materials suitable for use as cores arepharmaceutically acceptable and have appropriate dimensions andfirmness. Examples of such materials are polymers, inorganic substances,organic substances, saccharides and derivatives thereof. The route ofadministration can depend on the condition of the subject, co-medicationand the like.

Dosages of the compounds can depend on age, body weight, general healthconditions, sex, diet, dose interval, administration routes, excretionrate, combinations of drugs and conditions of the diseases treated,while taking these and other necessary factors into consideration.Generally, dosage levels of between about 10 μg per day to about 5000 mgper day, preferably between about 10 mg per day to about 1000 mg per dayof the compound are useful for the inhibition of CYP 2D6 enzymes.Typically, the pharmaceutical compositions of this invention will beadministered from about 1 to about 3 times per day or alternatively, asa continuous infusion. Such administration can be used as a chronic oracute therapy.

The amount of active ingredient that can be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. A typicalpreparation will contain from about 5% to about 95% active compound(w/w). Preferably, such preparations contain from about 20% to about 80%active compound.

While these dosage ranges can be adjusted by a necessary unit base fordividing a daily dose, as described above, such doses are decideddepending on the diseases to be treated, conditions of such diseases,the age, body weight, general health conditions, sex, diet of thepatient then treated, dose intervals, administration routes, excretionrate, and combinations of drugs, while taking these and other necessaryfactors into consideration. For example, a typical preparation willcontain from about 5% to about 95% active compound (w/w). Preferably,such preparations contain from about 10% to about 80% active compound.The desired unit dose of a composition of this invention is administeredonce or multiple times daily.

In some embodiments, the invention contemplates compositions andformulations comprising one or more of the compounds in combination withone or more other drugs that can be metabolized or degraded by CYP 2D6.

The CYP inhibitors of this invention can be administered to a patienteither as a single agent (for use with a separate dose of another drug)or in a combined dosage form with at least one other drug. Additionaldrugs also can be used to increase the therapeutic effect of thesecompounds.

Cyp inhibitors can also be used as standalone therapeutics forCyp-mediated diseases, or as prophylactic agents for preventing theproduction of toxic metabolites.

Such combination therapy in different formulations can be administeredsimultaneously, separately or sequentially. The Cyp inhibitors can beadministered prior to administration of the other drug to reduce Cyplevels and minimize degradation of the drug. In specific embodiments,the Cyp inhibitor is administered, 30 minutes, 1 hour, four hours,twelve hours or twenty four hours prior to initial administration of theother drug. The Cyp inhibitors tend to have a long half-life in vivo,presumably as a result of inhibiting their own metabolism. This meansthat once treatment has begun, the Cyp inhibitor may be administeredless frequently than the drug, although the skilled artisan willrecognize that different administration regiments may be needed inspecific situations. Alternatively, such combinations can beadministered as a single formulation, whereby the active ingredients arereleased from the formulation simultaneously or separately.

The following examples illustrate further the invention but, of course,should not be construed in any way of limiting its scope.

EXAMPLES Example 1 Synthetic Methods

The following experimental protocols are illustrative of the methodsused to synthesize compounds of the invention. Syntheses of thecompounds below are exemplified, although the skilled artisan willrecognize that these exemplary methods are of general applicability.

(1-Benzyl-2-hydroxy-3-isobutylamine-propyl)-carbamic acid tert-butylester 1 (1006 mg, 3.0 mmol, 1.0 equiv.) and Fmoc chloride (854 mg, 3.3mmol, 1.1 equiv.) were dissolved in dichloromethane (15 mL). To thesolution was added triethylamine (502 μL, 3.6 mmol, 1.2 equiv.) at roomtemperature. The mixture was stirred at the same temperature for 1 h,after which time the reaction was quenched through the addition of asmall amount of silica gel and dichloromethane. The mixture wasconcentrated in vacuo and the residue was purified by MPLC on silica gel(ethyl acetate in hexane, 0-100%) to afford the target 2 as a whitesolid (1270 mg, 76%). Mass 581 (MNa)⁺, and 459 (M-Boc)⁻. Purity 99%(HPLC).

To the solution of 2 (260 mg, 0.47 mmol, 1.0 equiv.) in dichloromethane(0.3 mL) was added trifluoroacetic acid (0.3 mL) at 0° C. Then themixture was stirred at room temperature for 30 min, after which time thesolution was diluted with dichloromethane (20 mL) and saturated NaHCO₃solution (10 mL) and the two layers separated. The organic phase waswashed twice with brine, dried over Na₂SO₄, and concentrated in vacuo toafford the crude product 3, which was used directly in the next step.

To a solution of 3 (210 mg, 0.46 mmol, 1.0 equiv.) in dichloromethane (2mL) was added benzofuran-5-sulfonyl chloride (4) (109 mg, 0.50 mmol, 1.1equiv.) and triethylamine (77 μL, 0.55 mmol, 1.2 equiv.). The mixturewas stirred at room temperature for 60 min and a small amount of silicagel was added. Then the solution was concentrated in vacuo. The residuewas purified by MPLC on silica gel (ethyl acetate in hexane, 0-60%) toafford the target 5 as a white solid (220 mg, 75%). Mass 639 (MH)⁺, and415 (M-FmocH)⁻. Purity 98% (HPLC).

A solution of 5 in piperidine (2.4 mL) was stirred at room temperaturefor 60 min and poured into 20 mL of cold water. The solution wasextracted with ethyl acetate. The combined organic phase was dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography (ethyl acetate/dichloromethane/methanol 5:5:1) toafford the target 6 as an oil (72 mg, 72%). Mass 417 (MH)⁺, 451 (MCI)⁻,415 (M-H)⁻. Purity 99% (HPLC).

Benzofuran-5-carbaldehyde (330 mg, 2.19 mmol, 1.0 equiv.) and4-aminopyridine (227 mg, 2.41 mmol, 1.1 equiv.) were combined in1,2-dichloroethane (22 mL) and treated with acetic acid (138 uL, 2.41mmol, 1.1 equiv.) and sodium triacetoxyborohydride (969 mg, 4.34 mmol,1.98 equiv.). The mixture was stirred at 60° C. overnight, and thenquenched by addition of saturated NaHCO₃ solution. The two phases wereseparated and the water layer was extracted twice with ethyl acetate.The combined organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified with flash columnchromatography on silica gel, eluting with ethylacetate/dichloromethane/methanol to afford the target 7 as a white solid(62 mg, 13%). Mass: 225 (MH)⁺. Purity >99% (HPLC).

To a solution of 2,2-dimethylpropane-1,3-diamine (2.0 g, 19.6 mmol) indichloromethane (20 ml) were added triethylamine (4.0 ml, 29.4 mmol) andbenzofuran-5-sulfonyl chloride (4.2 g, 19.6 mmol). The mixture wasstirred for 10 min at room temperature, quenched with saturated sodiumbicarbonate aqueous solution (20 ml), and extracted with dichloromethane(10 ml). The organic phase was washed with brine (30 ml), dried overMgSO₄, and concentrated in vacuo. MPLC on silica gel (dichloromethane30% methanol in dichloromethane) afforded 8 (4.2 g, 76%) as a whitesolid.

To a solution of 8 (1.0 g, 3.5 mmol) in methanol (15 ml) were addedisobutyraldehyde (702 μl, 7.7 mmol), acetic acid (440 μl, 7.7 mmol) andsodium acetate (631 mg, 7.7 mmol). The mixture was stirred for 30 min atrt and treated with sodium borohydride (529 mg, 14.0 mmol). After 30min, sodium bicarbonate (aq) (20 ml) was added to quench the reaction.The water phase was extracted with ethyl acetate (15 ml) and the organiclayer was washed with brine (20 ml), dried over magnesium sulfate andconcentrated in vacuo. MPLC on silica gel (hexanes→ethyl acetate)afforded 9 (690 mg, 68%) as a white solid. Mass 339 [MH]⁺, purity: 99%(HPLC).

To solution of 2-(Aminomethyl)-5-methylpyrazine (65 mg, 0.53 mmol) inmethanol (4 ml) were added benzofuran-5-carbaldehyde (77 mg, 0.53 mmol),acetic acid (33 μl, 0.58 mmol) and sodium acetate (48 mg, 0.58 mmol).The mixture was stirred for 30 min at rt and treated with sodiumborohydride (40 mg, 1.06 mmol). After 30 min, sodium bicarbonate (aq) (8ml) was added to quench the reaction. The aqueous phase was extractedwith ethyl acetate (10 ml) and the organic layer was washed with brine(10 ml), dried over magnesium sulfate and concentrated in vacuo.Preparative thin layer chromatography (dichloromethane:methanol=10:1)afforded 10 (102 mg, 75%) as a yellow oil. Mass 254 [MH]⁺, purity:100%(HPLC).

Variations, modifications, and other implementations of what isdescribed herein will occur to those of ordinary skill in the artwithout departing from the spirit and the scope of the invention.Accordingly, the invention is not to be limited only to the precedingillustrative descriptions.

1-36. (canceled)
 37. A compound represented by the formula:

wherein: X is [—N(D)-SO_(n)—]_(q), wherein n is 1 or 2 and q is 0 or 1;wherein when q is 0, R′ is C₁-C₆ alkylene, optionally substituted by upto 3 substituents independently selected from the group consisting ofC₁-C₃ alkyl, OH, O-alkyl, alkylamido, alkylcarbamoyl, halo, nitro,cyano, S-alkyl, aralkyl and heteroaralkyl; D is selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyland aralkyl; and R″ is selected from the group consisting of C₃-C₆cycloalkyl, C₃-C₆ cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyl or aralkyl,optionally substituted by up to 3 substituents independently selectedfrom the group consisting of OH, O-alkyl, alkylamido, alkylcarbamoyl,halo, nitro, cyano, S-alkyl, aralkyl and heteroaralkyl; or wherein whenq is 1, R′ is C₂-C₆ alkylene, optionally substituted by up to 3substituents independently selected from the group consisting of C₁-C₃alkyl, OH, O-alkyl, alkylamido, alkylcarbamoyl, halo, nitro, cyano,S-alkyl, aralkyl and heteroaralkyl; D is selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyland aralkyl; and R″ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,heteroaryl, heteroaralkyl or aralkyl, optionally substituted by up to 3substituents independently selected from the group consisting of OH,O-alkyl, alkylamido, alkylcarbamoyl, halo, nitro, cyano, S-alkyl,aralkyl and heteroaralkyl; or a pharmaceutically acceptable saltthereof.
 38. The compound of claim 37 wherein D is hydrogen orheteroaralkyl.
 39. A compound according to claim 37, wherein saidcompound is selected from the group consisting of:


40. The compound according to claim 37, wherein q is 0, and R′ ismethylene.
 41. The compound according to claim 40 wherein D is H orheteroaralkyl.
 42. The compound according to claim 41 wherein R″ isheteroaryl, or, heteroaralkyl.
 43. The compound according to claim 41wherein R″ is alkylcarbamoyl substituted C₁-C₆ alkyl.
 44. The compoundaccording to claim 37 wherein q is 1, and D is H or alkyl.
 45. Thecompound according to claim 44 wherein R″ is alkyl.
 46. A pharmaceuticalformulation comprising a pharmaceutically acceptable diluent, adjuvantor excipient, and a therapeutically effective amount of a compoundaccording to claim 37.